The topical use of NSAIDs in the treatment of ophthalmic diseases was first taught in U.S. Pat. No. 4,454,151. This US patent disclosed efficacious formulations with NaH2PO4H2O, Na2PO4H2O, NaCl, benzalkonium chloride (BAK) and sterilized water. However, these formulations were found to not have the stability required for shelf life in formulations.
Ocufen Ophthalmic solution, a non-patented medicament launched in 1988, is the first NSAID (flurbiprofen) approved by the FDA for ophthalmic use, and incorporates thimerosal as its preservative system. Thimerosal is an irritating compound (approximately 49% mercury by weight), and is known for its teratogenic side effects. New generations of ophthalmic formulations deprived from thimerosal are therefore needed.
U.S. Pat. No. 5,110,493 disclosed improved and stable ophthalmic solutions (but no emulsions) including NSAID and using BAK as preservative. This formulation comprises 0.001% to 10% of NSAID, 0.001% to 1% of preservative such as BAK, 0.001% to 1% of surfactant such as octoxynol 40, excipients and water. This formulation was shown to be stable for at least the minimum reasonable shelf life of such products. However, bioavailability is poor: typical dosage ranges for this formulation to treat an eye condition is disclosed to be about 2-10 drops of 0.1% solution of NSAID per day.
This raises the problem of bioavailability of topically instilled drugs such as NSAIDs. Most of these NSAIDs exhibit complex ocular formulations problem due to aqueous solubility limitations. Therefore, attempts have been made to improve ocular bioavailability of NSAIDs by designing new colloidal delivery systems based either on nanoparticles, and negatively or positively charged submicron emulsions.
Examples of such emulsions are disclosed in Klang et al (Journal of Controlled Release, 1999, 57:19-27): NSAID 0.1%, MCT 8.5%, Lipoid E80 1.2%, stearylamine 0.3%, alpha-tocopherol 0.02%, poloxamer 188 1%, glycerol 2.2.5% and water.
The Applicant worked on different ophthalmic emulsions for NSAIDs in order to obtain an emulsion having a better stability and providing a better ocular bioavailability of NSAIDs.
In US2006/0100288, the Applicant suggests that NSAID could be added in oil-in-water emulsions. However, the Applicant did not provide any working example.
The Applicant further worked on long chain quaternary ammonium compounds such as BAK, and noticed that the length of the alkyl chain was important with regards to the function performed by the quaternary ammonium compounds in an oil-in-water emulsion containing NSAIDs: acting on the length of the alkyl chain resulted in enhancing or reducing the cationic power of the quaternary ammonium compounds. Without wanting to be linked by any theory, the Applicant observed on working on oil-in-water emulsions containing NSAIDs, that long chain alkyl quaternary ammonium compounds were preferentially localized at the oil/water interface of the emulsions, resulting in (1) emulsions with higher zeta potential and (2) more stable emulsions.
In addition, the Applicant observed that an emulsion comprising NSAID and a quaternary ammonium halide in which the nitrogen atom is substituted by one or more alkyl group having at least 12, preferably 14 or 16, more preferably 16 carbon atoms provides a better ocular bioavailability compared to others formulations, which is of importance and resulted in the design of therapeutic emulsions having a content in oil of less than 6%, preferably of 5% or less, thus less irritating than the prior art emulsion.
Moreover, the Applicant noticed that the process for manufacturing NSAID containing emulsions at physiological pH (i.e. pH ranging from 6.8 to 7.4) was not leading to stable emulsion.
Therefore, stability of NSAID containing emulsions appeared to be a technical issue, for which no solution was provided in the prior art.